Nonsense mutations in SMPX, encoding a protein responsive to physical force, result in X-chromosomal hearing loss.
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Nonsense mutations in SMPX, encoding a protein responsive to physical force, result in X-chromosomal hearing loss. / Huebner, Antje K; Gandia, Marta; Frommolt, Peter; Maak, Anika; Wicklein, Eva M.; Thiele, Holger; Altmüller, Janine; Wagner, Florian; Viñuela, Antonio; Aguirre, Luis A; Moreno, Felipe; Maier, Hannes; Rau, Isabella; Giesselmann, Sebastian; Nürnberg, Gudrun; Gal, Andreas; Nürnberg, Peter; Hübner, Christian A; Ignacio, Del Castillo; Kurth, Ingo.
in: AM J HUM GENET, Jahrgang 88, Nr. 5, 5, 2011, S. 621-627.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Nonsense mutations in SMPX, encoding a protein responsive to physical force, result in X-chromosomal hearing loss.
AU - Huebner, Antje K
AU - Gandia, Marta
AU - Frommolt, Peter
AU - Maak, Anika
AU - Wicklein, Eva M.
AU - Thiele, Holger
AU - Altmüller, Janine
AU - Wagner, Florian
AU - Viñuela, Antonio
AU - Aguirre, Luis A
AU - Moreno, Felipe
AU - Maier, Hannes
AU - Rau, Isabella
AU - Giesselmann, Sebastian
AU - Nürnberg, Gudrun
AU - Gal, Andreas
AU - Nürnberg, Peter
AU - Hübner, Christian A
AU - Ignacio, Del Castillo
AU - Kurth, Ingo
PY - 2011
Y1 - 2011
N2 - The fact that hereditary hearing loss is the most common sensory disorder in humans is reflected by, among other things, an extraordinary allelic and nonallelic genetic heterogeneity. X-chromosomal hearing impairment represents only a minor fraction of all cases. In a study of a Spanish family the locus for one of the X-chromosomal forms was assigned to Xp22 (DFNX4). We mapped the disease locus in the same chromosomal region in a large German pedigree with X-chromosomal nonsyndromic hearing impairment by using genome-wide linkage analysis. Males presented with postlingual hearing loss and onset at ages 3-7, whereas onset in female carriers was in the second to third decades. Targeted DNA capture with high-throughput sequencing detected a nonsense mutation in the small muscle protein, X-linked (SMPX) of affected individuals. We identified another nonsense mutation in SMPX in patients from the Spanish family who were previously analyzed to map DFNX4. SMPX encodes an 88 amino acid, cytoskeleton-associated protein that is responsive to mechanical stress. The presence of Smpx in hair cells and supporting cells of the murine cochlea indicates its role in the inner ear. The nonsense mutations detected in the two families suggest a loss-of-function mechanism underlying this form of hearing impairment. Results obtained after heterologous overexpression of SMPX proteins were compatible with this assumption. Because responsivity to physical force is a characteristic feature of the protein, we propose that long-term maintenance of mechanically stressed inner-ear cells critically depends on SMPX function.
AB - The fact that hereditary hearing loss is the most common sensory disorder in humans is reflected by, among other things, an extraordinary allelic and nonallelic genetic heterogeneity. X-chromosomal hearing impairment represents only a minor fraction of all cases. In a study of a Spanish family the locus for one of the X-chromosomal forms was assigned to Xp22 (DFNX4). We mapped the disease locus in the same chromosomal region in a large German pedigree with X-chromosomal nonsyndromic hearing impairment by using genome-wide linkage analysis. Males presented with postlingual hearing loss and onset at ages 3-7, whereas onset in female carriers was in the second to third decades. Targeted DNA capture with high-throughput sequencing detected a nonsense mutation in the small muscle protein, X-linked (SMPX) of affected individuals. We identified another nonsense mutation in SMPX in patients from the Spanish family who were previously analyzed to map DFNX4. SMPX encodes an 88 amino acid, cytoskeleton-associated protein that is responsive to mechanical stress. The presence of Smpx in hair cells and supporting cells of the murine cochlea indicates its role in the inner ear. The nonsense mutations detected in the two families suggest a loss-of-function mechanism underlying this form of hearing impairment. Results obtained after heterologous overexpression of SMPX proteins were compatible with this assumption. Because responsivity to physical force is a characteristic feature of the protein, we propose that long-term maintenance of mechanically stressed inner-ear cells critically depends on SMPX function.
KW - Animals
KW - Humans
KW - Male
KW - Female
KW - Adolescent
KW - Child
KW - Child, Preschool
KW - Mice
KW - Mice, Inbred C57BL
KW - Age of Onset
KW - Genome-Wide Association Study
KW - Pedigree
KW - Alleles
KW - Hela Cells
KW - Haplotypes
KW - Genetic Linkage
KW - Codon, Nonsense
KW - Chromosomes, Human, X/genetics
KW - Cochlea
KW - Ear, Inner/embryology/metabolism
KW - Hair Cells, Auditory/metabolism
KW - Hearing Loss/genetics
KW - Muscle Proteins/genetics
KW - Animals
KW - Humans
KW - Male
KW - Female
KW - Adolescent
KW - Child
KW - Child, Preschool
KW - Mice
KW - Mice, Inbred C57BL
KW - Age of Onset
KW - Genome-Wide Association Study
KW - Pedigree
KW - Alleles
KW - Hela Cells
KW - Haplotypes
KW - Genetic Linkage
KW - Codon, Nonsense
KW - Chromosomes, Human, X/genetics
KW - Cochlea
KW - Ear, Inner/embryology/metabolism
KW - Hair Cells, Auditory/metabolism
KW - Hearing Loss/genetics
KW - Muscle Proteins/genetics
M3 - SCORING: Journal article
VL - 88
SP - 621
EP - 627
JO - AM J HUM GENET
JF - AM J HUM GENET
SN - 0002-9297
IS - 5
M1 - 5
ER -
